Recently, advances have been made in synthesizing stable proteins with novel sequences. Efforts to design proteins rely largely on knowledge of the physical properties that determine protein structure, such as the patterns of hydrophobic and hydrophilic residues in the sequence, salt bridges and hydrogen bonds, and secondary structural preferences of amino acids. Various approaches to apply these principles have been attempted. For example, helical proteins were generated and discussed in Regan, et al., Science 241:976-978 (1988) and an experimental method was developed using random mutagenesis and described in Kamtekar, et al., Science 262:1680-1685 (1993). Similarly, U.S. Pat. No. 6,708,120 discusses a method that starts with a protein backbone structure and then modifies the backbone structure by establishing a group of potential rotamers for each of the variable residue positions in the backbone. The process then quantitatively analyzes and evaluates the interaction of each of the potential rotamers with all or part of the remainder of the protein backbone. Through this process, the method attempts to generate a set of optimized protein sequences. Additionally, de novo protein design has been discussed that proposes fully automated sequence selection. Dahiyat, B. I., and Mayo, S. L., De novo Protein Design: Fully Automated Sequence Selection. Science, 278, 82 (1997). This work demonstrated a computational design algorithm based on physical-chemical potential functions and stereochemical constraints. The constraints were used to screen a combinatorial library of possible amino acid sequences for compatibility with a design target. Through this algorithm, non-wild type proteins were designed, as confirmed by BLAST searches, that had a compact well-ordered structure, in agreement with the design target.
Although these approaches have brought some clarity and discipline to the process of peptide design, the standard approach today is still to synthesize new peptides by creating synthesized peptides that look very similar to a known peptide having a particular function or purpose. The hope is that the synthesized peptide will have similar functionality as the naturally occurring peptide, and minimal or no side effects. The standard method is still employed today because synthesizing peptides is relatively simple and the currently developed approaches for computationally determining peptide sequences of interest are difficult to implement and offer only marginal improvement over heuristic sequence selection. Further, the existing processes have been limited in scope in as much as they typically begin from a starting point that is related to or defined by a single protein or peptide of interest. This tends to provide a narrow focus for the later development processes, and keeps newly developed proteins tightly bound to the selected seed sequence.
Thus, there is a need in the art for sequence design processes that provide a more comprehensive and methodical approach to protein design.